Jordan Ensz ’19 and Rachel Lin ’18

Schizophrenia is a disease that many times is associated with an insane asylum or tragic instances of violence in the news. Media and other outlets tend to portray this illness in a negative lens that only reinforces the stigmas that have surrounded it for decades using headlines like “Schizophrenic stabbed brother, nine, to death hours after health workers said he was no threat” and “1,200 killed by mental patients”. But instead of encouraging the fear and obscurity that have been built up around schizophrenia, increasing awareness and knowledge can have a huge effect on how people with the disorder are integrated into society. Both social stigmas and acceptance movements can impact the research that goes into finding the cause and treatments to help them live a better life.

Schizophrenia is a mental disorder that occurs in up to 1% of the world’s population and patients are diagnosed with symptoms including hallucinations, delusions, apathy, and cognitive dysfunction. This disorder can greatly affect all aspects of life; however, patients can live a relatively normal life if they are properly diagnosed and treated. Researchers are now looking for more ways to manage the disease and to figure out the possible mechanisms — genetic and epigenetic — in order to further our understanding of this disease as a whole.

While genetics refers to the actual DNA sequence of a living organism, epigenetics refers to extra pieces on the DNA that determine which genes are on or off without altering the DNA sequence itself. The idea of turning genes on and off is known as gene expression, similar to speaking certain sentences of a book out loud meaning it is on, and reading it in your head meaning it is off. Either way, the sentences are all on the page, you’re just putting more emphasis on certain ones, like how only certain genes are used in DNA. The combination of the different epigenetic components that can occur are known as epigenomes. Each student in a biology class will have the same textbook, but they might all highlight different parts that they think are important or cross out things they already know, creating slightly different books that all still have the same text in it. Recent studies have shown that there may be a connection between schizophrenia and epigenetics. Schizophrenia has behavioral as well as physical effects on patients, and the image below shows the MRI scan of a schizophrenia brain compared to a healthy brain; notice the loss in brain tissue shown by the enlarged dark areas in the schizophrenia brain:

These physical brain changes shown above can be seen in schizophrenia patients. Schizophrenia patients have lower amounts of certain “controllers” called reelin and GAD67. These controllers can help change which genes are on and off. Why do these patients have less? Too many genes are crossed out in these patients so they are not getting the right things read and created by their brains. Schizophrenic patients have too many DNA methyltransferases (DNMTs), which are like pencils that cross out genes by adding a chemical called a methyl group which blocks the genes from being read. The DNA, which is like the words that make up a sentence, was not erased, but is no longer part of the sentence being read, or what is being expressed in the brain. Another mechanism to change the epigenome and the genes expressed is through adding acetyl groups, which generally activates, or increases, gene expression, similar to highlighting words while reading. The words were always there, but now they are highlighted to be expressed by DNA machinery. It has been shown that in schizophrenic patients, there is a higher amount of the machinery that removes acetyl groups. This causes the gene to be expressed less just as adding methyl groups does. The following image depicts how methylation and acetylation can turn genes on or off, noting that adding methyl groups causes genes to turn off and adding acetyl groups causes genes to turn on:

Through these various epigenetic mechanisms described above, the epigenome is changed, and the changes discussed above are present in schizophrenic patients.

Early life stress and prenatal stress, or stress on the mother while she is pregnant, can also go on to show symptoms of schizophrenia and the epigenetic changes described above. These types of stress can be risk factors for schizophrenia. Specifically, with patients that had dealt with early life stress such as abuse or neglect, there is more machinery to remove acetyl groups, called Histone Deacetylaces (HDACs), in certain brain regions. By removing these acetyl groups, it is like removing the highlighting from a sentence. It is still there, but it isn’t being expressed as much. Studies have shown that decreasing the activity of the machinery that removes acetyl groups lessens schizophrenic symptoms in mice. If applied to humans, the information from these studies can be used to potentially create therapy options for schizophrenic patients to decrease symptoms. Stress on the mother while she is pregnant can cause changes in DNA methylation in her child that is similar to the patterns seen in schizophrenic patients with more genes crossed out. This stress on the mother causes DNA methylation machinery levels in her baby to increase, which causes the “controller” (reelin and GAD67) levels to go down, similar to what we would see in schizophrenic patients. The studies we looked at compared the patterns of these babies to adults with schizophrenia, and so this could lead to new information about risk factors of schizophrenia and possible ways to prevent it using drugs or other interventions.

Patients with schizophrenia can nowadays lead relatively normal lives with a proper treatment plan that usually involves antipsychotic drugs combined with other therapies. But with more research, new treatments have been thought of that use blockers of the machinery to remove acetyl groups, turning genes off, or drugs that cause demethylation, turning genes on. It is like putting the cap on the pen so it can’t cross anything out. These treatments can stop acetyl groups from being removed or methyl groups from being added, and this causes certain genes to be read more. Clozapine, a newer antipsychotic drug typically used in these treatments, has been shown to help remove methyl groups, allowing those genes to be turned on again. Using the findings from these experiments, these drugs have helped to greatly decrease the symptoms seen in schizophrenia. These include things like the lower levels of GAD67 and reelin (the “controllers”), and the behaviors they cause in the patient, which means that these extra chemicals being changed around the DNA (the epigenetic mechanisms) might cause part of the disease. This knowledge can be used in both treating the disease in the future, and understanding the illness.

The stigma that surrounds schizophrenia also extends to other mental illnesses, despite recent movements to increase understanding and acceptance of them. What is also common across many mental illnesses is that there is research being done to find the causes, with these extra chemical pieces being a big focus for these studies. For example, studies of rats that show signs of of depression and anxiety have shown high levels of methylation of certain genes, which could mean they have too many genes being crossed out. There have also been studies that look at the pups of mother rats with depression and those without depression, and they show that when the pups are raised by a different mother, they have different behaviors than if they were raised by their birth mother. When they looked at the rat’s DNA more closely, it was discovered that different methylation, or patterns of crossing out, was occuring based on who raised the pup. The different methylation meant more or less genes were crossed out, which ultimately changed their behavior and shows that it wasn’t through the DNA itself, but the extra chemical changes. The pups raised by more abusive mothers had more methylation, turning genes off, and showed more signs of depression than those raised by caring mothers. This could mean there is an epigenetic mechanism to depression and anxiety. The pups raised by abusive mothers also showed a fear of open spaces and would huddle in dark, enclosed areas, which shows increased anxiety. Connecting the behaviors of these disorders with epigenetic traits lets scientists find a possible cause for how they occur, and to create treatments and therapies to reduce the negative effects that the mental illnesses cause.

Although schizophrenia is a well heard of disease, the how it works and treatments are still not well researched and are still being studied heavily. The discovery of epigenetic mechanisms for schizophrenia could have massive implications for the treatment of patients in the future, and lead to a better understanding of the risk factors for schizophrenia. The stigma surrounding mental illnesses such as schizophrenia, depression, and anxiety is in part caused by the lack of knowledge regarding the root causes behind these diseases. Finding a possible epigenetic link that illuminates the root of these diseases is an important step in understanding these diseases, and perhaps even more importantly, changing how we as a public view these diseases and the people who have them.

References

  1. Correction for Bahari-Javan et al., HDAC1 links early life stress to schizophrenia-like phenotypes. (2017). Proceedings of the National Academy of Sciences, 114(29). doi:10.1073/pnas.1711340114
  2. Matrisciano, F., Tueting, P., Dalal, I., Kadriu, B., Grayson, D. R., Davis, J. M., . . . Guidotti, A.       (2013). Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice. Neuropharmacology, 68, 184-194. doi:10.1016/j.neuropharm.2012.04.013
  3. Qiu, Xiaoyan, et al. “Histone Deacetylases Inhibitors (HDACis) as Novel Therapeutic Application in Various Clinical Diseases.” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 72, 4 Jan. 2017, pp. 60–72., doi:10.1016/j.pnpbp.2016.09.002.
  4. Roth, T. L., Lubin, F. D., Funk, A. J., & Sweatt, J. D. (2009). Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene. Biological Psychiatry, 65(9), 760-769. doi:10.1016/j.biopsych.2008.11.028
  5. Roth, Tania L., et al. “Epigenetic Mechanisms in Schizophrenia.” Biochimica Et Biophysica Acta (BBA) – General Subjects, vol. 1790, no. 9, Sept. 2009, pp. 869–877., doi:10.1016/j.bbagen.2009.06.009.
  6. Swathy, Babu, et al. “Understanding the Influence of Antipsychotic Drugs on Global Methylation Events and Its Relevance in Treatment Response.” Epigenomics, vol. 10, no. 3, 18 Jan. 2018, pp. 233–247., doi:10.2217/epi-2017-0086.
  7. Tremolizzo, L., Carboni, G., Ruzicka, W. B., Mitchell, C. P., Sugaya, I., Tueting, P., . . . Guidotti, A. (2002). An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proceedings of the National Academy of Sciences, 99(26), 17095-17100. doi:10.1073/pnas.262658999
  8. Tremolizzo, L., Doueiri, M., Dong, E., Grayson, D. R., Davis, J., Pinna, G., . . . Guidotti, A. (2005). Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice. Biological Psychiatry, 57(5), 500-509. doi:10.1016/j.biopsych.2004.11.046

Multimedia

(1)Beattie, Elizabeth. “The Language of Mental Illness Is Broken.” Overland Literary Journal, 21 Apr. 2016, overland.org.au/2016/04/the-language-of-mental-illness-is-broken/.

(2)“Kingston Charity Criticises Sun’s ‘1,200 Killed by Mental Patients’ Headline.” Surrey Comet, 9 Oct. 2013, www.surreycomet.co.uk/news/10728044.Kingston_charity_criticises_Sun_s__1_200_killed_by_mental_patients__headline/.

(3) Aubrey Hill – Brain Plasticity – AP Psych 3B. (n.d.). Retrieved March 20, 2018, from https://sites.google.com/a/cms.k12.nc.us/ap-psych-3b/aubrey-hill—brain-plasticity

(4)Diagram created by Jordan Ensz

(5) Babenko, O., Kovalchuk, I., & Metz, G. A. (2015). Stress-induced perinatal and transgenerational epigenetic programming of brain development and mental health. Neuroscience & Biobehavioral Reviews, 48, 70-91. doi:10.1016/j.neubiorev.2014.11.013

Featured Image Source

Aubrey Hill – Brain Plasticity – AP Psych 3B. (n.d.). Retrieved March 20, 2018, from https://sites.google.com/a/cms.k12.nc.us/ap-psych-3b/aubrey-hill—brain-plasticity

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